Th17 cells play important roles in immunity, tissue inflammation and autoimmune diseases. The intestine is the most Th17 cell-enriched organ in the body. Therefore, investigation into the migration and function of Th17 cells in the gut would yield important information on the functions of Th17 cells in regulation of immune responses and immune tolerance in the intestine. It is unknown how Th17 cells are induced, maintained and localized in the gut. This is a significant problem in our understanding and control of this important T cell lineage. The central hypothesis of this application is that trafficking receptors play important roles in regulation of migration, induction, and/or maintenance of Th17 cells in the intestine. Our rationale is that it will become possible to more effectively control inflammatory diseases and infection in the gut by regulating the migration, induction and maintenance of gut Th17 cells after the proposed research is completed. Among the trafficking receptors, we will focus our research on CCR6, CCR9 and 1427. CCR6 is the receptor that is characteristically expressed by most Th17 cells and binds the chemokine CCL20 specifically expressed in the inductive sites of the intestine. CCR9 is a retinoic acid-induced trafficking receptor and plays potentially important roles in Th17 cell migration to certain effector sites of the intestine. 1427 is another retinoic-induced receptor potentially important for migration of Th17 cells to both inductive and effector sites. It is likely that the three receptors cooperatively regulate subset-specific distribution of Th17 cells in various anatomic compartments of the intestine. There are three aims: Specific aim #1. Determine the mechanism for coordinated regulation of the expression and/or activity of CCR6, CCR9 and 1427 in Th17 cells. Specific aim #2. Determine the individual and coordinated roles of CCR6, CCR9 and 1427 in Th17 cell migration to various microanatomic sites within the intestine. Specific aim #3. Determine the roles of CCR6, CCR9 and 1427 in induction, maintenance and effector function of Th17 cells in the gut. It is expected to yield novel knowledge regarding the trafficking receptor requirement for migration, induction and maintenance of gut Th17 cells. The project will also provide novel strategies to control the migration of Th17 cells and their differentiation and activities in specific anatomic sites of the gut. This problem has primary importance to the inflammatory pathology and infection associated with the gut (e.g. inflammatory bowel diseases and infection) but is important also for inflammatory diseases in other tissue sites as well. PUBLIC HEALTH RELEVANCE: Th17 cells have recently been recognized as a major lineage of immune cells that regulate inflammation in the body. The research aims to provide novel strategies to control the migration, differentiation and function of Th17 cells in the intestine, which are particularly relevant to inflammatory bowel diseases. The outcomes can also be applied to control of Th17-cell-regulated inflammation and immunity in other tissues.